Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.
Epidermal growth factor (EGF) is a widely distributed growth factor that in cancer, can stimulate cancer-cell proliferation, block apoptosis, activate invasion and metastasis, and stimulate angiogenesis (Citri, et al., Nat. Rev. Mol. Cell. Biol. 7:505, 2006; Hynes, et al., Nat. Rev. Cancer 5:341, 2005). The EGF receptor (EGFR or ErbB) is a transmembrane, tyrosine kinase receptor that belongs to a family of four related receptors. The majority of human epithelial cancers are marked by functional activation of growth factors and receptors of this family (Ciardiello, et al., New Eng. J. Med. 358: 1160, 2008) so that EGF and EGFR are natural targets for cancer therapy. The human epidermal growth factor receptor (HER) tyrosine kinase family consists of four structurally related cellular receptors: the epidermal growth factor receptor (EGFR;HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4. Quinazolines are a known class of kinase inhibitors with utility for the treatment of cancer, angiogenesis disorders, and inflammatory disorders. To this end, attempts have been made to identify small molecules which act as protein kinase inhibitors. For example, quinazoline derivatives (PCT WO 00177104; US20050250761; WO2004069791) have been described as HER kinase inhibitors.
EGFR inhibitors erlotinib and gefitinib as well as the dual EGFR/HER2 inhibitor lapatinib are FDA-approved cancer drugs that are effective against multiple solid tumor cancers. However, their effectiveness is also limited by the drug resistance that frequent emerges following treatment point mutations in the kinase domain of EGFR as well as upregulation of by-pass signaling pathways are frequently observed resistance mechanisms in patients treated with gefitinib and erlotinib. A single point mutation at the gatekeeper position, T790M in EGFR kinase domain accounts for approximately 50% of acquired resistance.
Thus, the compounds that can inhibit mutant protein kinases such as EGFR T790M activity with improved efficacy or overcoming drug resistance are highly desired.
Bruton's tyrosine kinase (Btk) plays a key role in promoting B cell proliferation and survival through participation in the B cell receptor (BCR) signaling pathway and represents a promising new drug target. Targeted therapies that suppress BCR signaling have emerged as promising agents in the treatment of several B cell malignancies. To this end, attempts have been made to identify small molecules which act as Btk inhibitors. For example, U.S. Pat. No. 7,982,036 describes 4,6-disubstituted pyrimidine compounds as useful kinase inhibitors targeting the Tec kinase family. The disclosed compounds include Btk inhibitors. Another class of Btk inhibitors has been disclosed in U.S. Pat. No. 8,088,781.
Thus, the compounds that can inhibit protein kinases such as Bruton's tyrosine kinase (Btk) activity are highly desired.